Biheteroaryl inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention is directed to compounds of the formula A which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras: ##STR1## The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

This is a provisional application Ser. No. 60/014,592 filed Apr. 3,1996, and a provisional application Ser. No. 60/022,587 filed Jul. 24,1996.

BACKGROUND OF THE INVENTION

The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of asignalling pathway that links cell surface growth factor receptors tonuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a conformational change. The GTP-bound form of Raspropagates the growth stimulatory signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are found in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are defective in theirGTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational famesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also famesylated. James, et al., havealso suggested that there are famesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin four general classes (S. Graham, Expert Opinion Ther. Patents, (1995)5:1269-1285). The first are analogs of farnesyl diphosphate (FPP), whilea second class of inhibitors is related to the protein substrates (e.g.,Ras) for the enzyme. Bisubstrate inhibitors and inhibitors offarnesyl-protein transferase that are non-competitive with thesubstrates have also been described. The peptide derived inhibitors thathave been described are generally cysteine containing molecules that arerelated to the CAAX motif that is the signal for protein prenylation.(Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS,88:732-736 (1991)). Such inhibitors may inhibit protein prenylationwhile serving as alternate substrates for the farnesyl-proteintransferase enzyme, or may be purely competitive inhibitors (U.S. Pat.No. 5,141,851, University of Texas; N. E. Kohl et al., Science,260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). Ingeneral, deletion of the thiol from a CAAX derivative has been shown todramatically reduce the inhibitory potency of the compound. However, thethiol group potentially places limitations on the therapeuticapplication of FPTase inhibitors with respect to pharmacokinetics,pharmacodynamics and toxicity. Therefore, a functional replacement forthe thiol is desirable.

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 A1).

It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels (JPH7-112930).

It is, therefore, an object of this invention to develop low molecularweight compounds that will inhibit farnesyl-protein transferase andthus, the post-translational farnesylation of proteins. It is a furtherobject of this invention to develop chemotherapeutic compositionscontaining the compounds of this invention and methods for producing thecompounds of this invention.

SUMMARY OF THE INVENTION

The present invention comprises peptidomimetic biheteroaryl-containingcompounds which inhibit the farnesyl-protein transferase. Furthercontained in this invention are chemotherapeutic compositions containingthese farnesyl transferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the formula A:##STR2##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the fanesylation of the oncogeneprotein Ras. In a first embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula A: ##STR3##wherein: from 1-2 of f(s) are independently N or N→O, and the remainingf's are independently CH;

from 1-3 of g(s) are independently N or N→O, and the remaining g's areindependently CR⁶ ;

R¹ and R² are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, R¹¹ C(O)O--, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰--;

R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

each R⁶ is independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R⁶ on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --;

provided that when R³, R⁴, R⁵ or R⁶ is unsubstituted or substitutedheterocycle, attachment of R³, R⁴, R⁵, or R⁶ to the 6-memberedheteroaryl ring, is through a substitutable heterocycle ring carbon;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR4## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is independently selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, Br, R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle;

X is a bond, --CH═CH--, O, --C(═O)--, --C(O)NR⁷ --, --NR⁷ C(O)--,--C(O)O--, --OC(O)--, --C(O)NR⁷ C(O)--, --NR⁷ --, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention is illustratedby the following formula A: ##STR5## wherein: from 1-2 of f(s) areindependently N or N→O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N→O, and the remaining g's areindependently CR⁶ ;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

each R⁶ is independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R⁶ on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --;

provided that when R³, R⁴, R⁵ or R⁶ is unsubstituted or substitutedheterocycle, attachment of R³, R⁴, R⁵, or R⁶ to the 6-memberedheteroaryl ring, is through a substitutable heterocycle ring carbon;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR6## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --; (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a heteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a substitutablering carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl orisoquinolinyl;

X is a bond, O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷ C(O)--, --NR⁷--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2or 3;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention areillustrated by the formula B: ##STR7## wherein: from 1-2 of f(s) areindependently N or N→O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N→O, and the remaining g's areindependently CR⁶ ;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ --,--N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

each R⁶ is independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R⁶ on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --;

provided that when R³, R⁴ or R⁶ is unsubstituted or substitutedheterocycle, attachment of R³, R⁴ or R⁶ to the 6-membered heteroarylring, is through a substitutable heterocycle ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰⁻⁻, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and provided that V is not hydrogen if A¹ isS(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; provided that when V is heterocycle, attachment of V to R⁸and to A¹ is through a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

Another preferred embodiment of the compounds of this invention areillustrated by the formula C: ##STR8## wherein: from 1-2 of f(s) areindependently N or N→O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N→O, and the remaining g's areindependently CR⁶ ;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

each R⁶ is independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R⁶ on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --; provided that when R³, R⁴ or R⁶ is unsubstituted orsubstituted heterocycle, attachment of R³, R⁴ or R⁶ to the 6-memberedheteroaryl ring, is through a substitutable heterocycle ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a substitutablering carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula D: ##STR9##wherein: from 1-2 of f(s) are independently N or N→O, and the remainingf's are independently CH;

from 1-3 of g(s) are independently N or N→O, and the remaining g's areindependently CR⁶ ;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

each R⁶ is independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹¹ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ C(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R⁶ on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --;

provided that when R³ or R⁶ is unsubstituted or substituted heterocycle,attachment of R³ or R⁶ to the 6-membered heteroaryl ring, is through asubstitutable heterocycle ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

n is 0 or 1; provided that n is not 0 if A¹ is a bond, O, --N(R¹⁰)-- orS(O)_(m) ;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In another more preferred embodiment of this invention, the inhibitorsof farnesyl-protein transferase are illustrated by the formula E:##STR10## wherein: from 1-2 of f(s) are independently N or N→O, and theremaining f's are independently CH;

from 1-3 of g(s) are independently N or N→O, and the remaining g's areindependently CR⁶ ;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

each R⁶ is independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R⁶ on adjacent carbon atoms arecombined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R³ or R⁶ is unsubstituted or substituted heterocycle,attachment of R³ or R⁶ to the 6-membered heteroaryl ring, is through asubstitutable heterocycle ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

n is 0 or 1;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula F: ##STR11##wherein: from 1-2 of f(s) are independently N or N→O, and the remainingf's are independently CH;

from 1-3 of g(s) are independently N or N→O, and the remaining g's areindependently CR⁶ ;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, CH₃ and CF₃ ;

each R⁶ is independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ aLkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R⁶ on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --;

provided that when R³ or R⁶ is unsubstituted or substituted heterocycle,attachment of R³ or R⁶ to the 6-membered heteroaryl ring, is through asubstitutable heterocycle ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula G: ##STR12##wherein: from 1-2 of f(s) are independently N or N→O, and the remainingf's are independently CH;

from 1-3 of g(s) are independently N or N→O, and the remaining g's areindependently CR⁶ ;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle or C₃ -C₁₀ cycloalkyl

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, CH₃ and CF₃ ;

each R⁶ is independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R⁶ on adjacent carbon atoms arecombined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R³ or R⁶ is unsubstituted or substituted heterocycle,attachment of R³ or R⁶ to the 6-membered heteroaryl ring, is through asubstitutable heterocycle ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

m is 0, 1 or 2; and

n is 0 or 1;

or the pharmaceutically acceptable salts thereof.

Specific examples of the compounds of the invention are:

1-(2- Pyrid-2-yl!pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole ##STR13##N-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-5-(pyrid-2-yl)-2-amino-pyrimidine##STR14## or the pharmaceutically acceptable salts thereof.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. When any variable (e.g. aryl, heterocycle, R¹, R²etc.) occurs more than one time in any constituent, its definition oneach occurence is independent at every other occurence. Also,combinations of substituents/or variables are permissible only if suchcombinations result in stable compounds.

As used herein, "alkyl" and the alkyl portion of aralkyl and similarterms, is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms; "alkoxy" represents an alkyl group of indicated number of carbonatoms attached through an oxygen bridge.

As used herein, "cycloalkyl" is intended to include non-aromatic cyclichydrocarbon groups having the specified number of carbon atoms. Examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number ofcarbon atoms and having one or several double bonds. Examples of alkenylgroups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,geranylgeranyl and the like.

"Alkynyl" groups include those groups having the specified number ofcarbon atoms and having one triple bonds. Examples of alkynyl groupsinclude acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.

"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl," and the aryl portion of aroyl and aralkyl, isintended to mean any stable monocyclic or bicyclic carbon ring of up to7 members in each ring, wherein at least one ring is aromatic. Examplesof such aryl elements include phenyl, naphthyl, tetrahydronaphthyl,indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. Examples ofsuch heterocyclic elements include, but are not limited to, azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,2-oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl,pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 members in each ring, wherein atleast one ring is aromatic and wherein from one to four carbon atoms arereplaced by heteroatoms selected from the group consisting of N, O, andS. Examples of such heterocyclic elements include, but are not limitedto, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, andthienyl.

As used herein in the definition of R⁷, the substituted C₁₋₈ alkyl,substituted C₃₋₆ cycloalkyl, substituted aroyl, substituted aryl,substituted heteroaroyl, substituted arylsulfonyl, substitutedheteroarylsulfonyl and substituted heterocycle include moietiescontaining from 1 to 3 substituent s in addition to the point ofattachment to the rest of the compound.

As used herein, when no specific substituents are set forth, the terms"substituted aryl", "substituted heterocycle" and "substitutedcycloalkyl" are intended to include the cyclic group which issubstituted on a substitutable ring carbon atom with 1 or 2substitutents selected from the group which includes but is not limitedto F, Cl, Br, CF₃, NH₂, N(C₁ -C₆ alkyl)₂, NO₂, CN, (C₁ -C₆ alkyl)O--,--OH, (C₁ -C₆ alkyl)S(O)_(m) --, (C₁ -C₆ alkyl)C(O)NH--, H₂ N--C(NH)--,(C₁ -C₆ alkyl)C(O)--, (C₁ -C₆ alkyl)OC(O)--, N₃,(C₁ -C₆ alkyl)OC(O)NH--,phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl,furyl, isothiazolyl and C₁ -C₂₀ alkyl.

Lines drawn into the ring systems from substituents (such as from R³, R⁴etc.) means that the indicated bond may be attached to any of thesubstitutable ring carbon atoms.

The moiety designated by the following structure ##STR15## represents anaromatic 6-membered heterocyclic ring and includes the following ringsystems: ##STR16##

The moiety designated by the following structure ##STR17## represents anaromatic 6-membered heterocyclic ring and includes the following ringsystems: ##STR18## wherein it is understood that one of the ring carbonatoms is substituted with ##STR19## Preferably, the aromatic 6-memberedheterocyclic ring is a pyridyl ring.

The moiety designated by the following structure ##STR20## represents anaromatic 6-membered heterocyclic ring and includes the following ringsystems: ##STR21## wherein R⁶ is as defined hereinabove.

The moiety described as ##STR22## where any two of R⁶ on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH--, --(CH₂)₄ -- and --(CH₂)₄ -- includes, but is not limitedto the following structures: ##STR23## It is understood that such fusedring moieties may be further substituted by the remaining R⁶ s asdefined hereinabove.

Preferably, the "terminal" aromatic 6-membered heterocyclic ring is apyridyl ring.

Preferably, R¹ and R² are independently selected from: hydrogen, R¹¹C(O)O--, --N(R¹⁰)₂, R¹⁰ C(O)NR¹⁰ --, R¹⁰ O-- or unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted phenyl,--N(R¹⁰)₂, R¹⁰ O-- and R¹⁰ C(O)NR¹⁰ --.

Preferably, R³ is selected from:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, CN, NO₂,R¹⁰ C(O)-- or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --.

Preferably, R⁴ is selected from: hydrogen, halogen, trifluoromethyl,trifluoromethoxy and C₁ -C₆ alkyl.

Preferably, R⁵ is hydrogen.

Preferably, R⁶ is independently selected from:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, CN, NO₂, R¹⁰ C(O)-- or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl, C₃ -C₁₀cycloalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)-- or --N(R¹⁰)₂ ; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --.

Preferably, R⁸ is independently selected from:

a) hydrogen, and

b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁ -C₆perfluoroalkyl or CN.

Preferably, R⁹ is hydrogen, halogen, CF₃ or methyl.

Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, A¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)-- and--N(R¹⁰)S(O)₂ --.

Preferably, V is selected from hydrogen, heterocycle and aryl. Morepreferably, V is phenyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl,pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W isselected from imidazolyl and pyridyl.

Preferably, n and r are independently 0, 1, or 2.

Preferably s is 0.

Preferably t is 1.

Preferably from 1-2 of f(s) are independently N, and the remaining fsare independently CH.

Preferably from 1-3 of g(s) are independently N, and the remaining g'sare independently CR⁶. Preferably, the moiety ##STR24## is selectedfrom: ##STR25##

It is intended that the definition of any substituent or variable (e.g.,R¹, R², R⁹, n, etc.) at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. Thus,--N(R¹⁰)₂ represents --NHH, --NHCH₃, --NHC₂ H₅, etc. It is understoodthat substituents and substitution patterns on the compounds of theinstant invention can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be readilysynthesized by techniques known in the art, as well as those methods setforth below, from readily available starting materials.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared either by ion exchange chromatography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the Schemes 1-12, in addition toother standard manipulations such as ester hydrolysis, cleavage ofprotecting groups, etc., as may be known in the literature orexemplified in the experimental procedures. Substituents R³, R⁶ and R⁸,as shown in the Schemes, represent the substituents R³, R⁴, R⁵, R⁶ andR⁸ ; although only one such R³, R⁶ or R⁸ is present in the intermediatesand products of the schemes, it is understood that the reactions shownare also applicable when such aryl or heteroaryl moieties containmultiple substituents.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. The reactions described in the Schemes are illustrativeonly and are not meant to be limiting. Other reactions useful in thepreparation of heteroaryl moieties are described in "ComprehensiveOrganic Chemistry, Volume 4: Heterocyclic Compounds" ed. P. G. Sammes,Oxford (1979) and references therein. Aryl-aryl coupling is generallydescribed in "Comprehensive Organic Functional Group Transformations,"Katritsky et al. eds., pp 472-473, Pergamon Press (1995).

Synopsis of Schemes 1-12:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 1-12 illustrate synthesis of the instant biheteroaryl compoundwhich incorporate a preferred benzylimidazolyl sidechain. Thus, inScheme 1, for example, a biheteroaryl intermediate that is notcommercially available may be synthesized by methods known in the art.Thus, a suitably substituted pyridyl boronic acid I may be reacted underSuzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with asuitably substituted halogenated nicotinic acid, such as4-bromo-nicotinic acid, to provide the biheteroaryl carboxylic acid II.The acid may be reduced and the triflate of the intermediate alcohol IIImay be formed in situ and coupled to a suitably substitutedbenzylimidazolyl IV to provide, after deprotection, the instant compoundV.

Schemes 2-4 illustrate other methods of synthesizing the key alcoholintermediates, which can then be processed as described in Scheme 1.Thus, Scheme 2 illustrates the analogous series of bihetero-aryl alcoholforming reactions starting with the methyl nicotinate boronic acid andthe "terminal" heteroaryl moiety employed in the Suzuki coupling as thehalogenated reactant. Such a coupling reaction is also compatible whenone of the reactants incorporates a suitably protected hydroxylfunctionality as illustrated in Scheme 3.

Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed toform the biheteroaryl component of the instant compounds, as shown inScheme 4. Thus, a suitably substituted zinc bromide adduct may becoupled to a suitably substituted heteroaryl halide in the presence ofnickel (II) to provide the biheteroaryl VII. The heteroaryl halide andthe zinc bromide adduct may be selected based on the availability of thestarting reagents.

Scheme 5 illustrates the preparation of the pyridylmethanol intermediatestarting with the 3-methyl pyridine.

As illustrated in Scheme 6, the sequence of coupling reactions may bemodified such that the heteroaryl-heteroaryl bond is formed last. Thus,a suitably substituted imidazole may first be alkylated with a suitablysubstituted benzyl halide to provide intermediate VIII. IntermediateVIII can then undergo Suzuki type coupling to a suitably substitutedpyridyl boronic acid.

Scheme 7 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole IX may be selectivelyiodinated to provide the 5-iodoimidazole X. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate XI. Intermediate XI can then undergo the alkylationreactions that were described hereinabove.

Scheme 8 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the biaryl via an alkyl amino,sulfonamide or amide linker. Thus, the 4-aminoalkyl-imidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated biheteroaryl moieties to provide the instant compoundsshown.

Compounds of the instant invention wherein the A¹ (CR¹ 2)_(n) A² (CR¹2)_(n) linker is oxygen may be synthesized by methods known in the art,for example as shown in Scheme 9. The suitably substituted phenol XIVmay be reacted with methyl N-(cyano)methanimidate to provide the4-phenoxyimidazole XV. After selective protection of one of theimidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Scheme 10 illustrates an analogous series of reactions wherein the (CR²2)_(p) X(CR² 2)_(p) linker of the instant compounds is oxygen. Thus, asuitably substituted halopyridinol, such as 3-chloro-2-pyridinol, isreacted with methyl N-(cyano)methanimidate to provide intermediate XVI.Intermediate XVI is then protected and, if desired to form a compound ofa preferred embodiment, alkylated with a suitably protected benzyl. Theintermediate XVII can then be coupled to a heteroaryl moiety by Suzukichemistry to provide the instant compound.

Compounds of the instant invention wherein the A¹ (CR¹ 2)_(n) A² (CR¹2)_(n) linker is a substituted methylene may be synthesized by themethods shown in Scheme 11. Thus, the N-protected imidazolyl iodideXVIII is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol XIX. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 1) provides the instant compound XX. If other R¹ substituent sare desired, the acetyl moiety can be manipulated as illustrated in theScheme.

Scheme 12 illustrates the use of halogenated 2-amino-pyrimidine in thepreapration of compounds of the instant invention. ##STR26##

The instant compounds are useful as pharmaceutical agents for mammals,especially for humans. These compounds may be administered to patientsfor use in the treatment of cancer. Examples of the type of cancer whichmay be treated with the compounds of this invention include, but are notlimited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloidleukemias and neurological tumors. Such tumors may arise by mutations inthe ras genes themselves, mutations in the proteins that can regulateRas activity (i.e., neurofibromin (NF-1), neu, scr, abl, lck, fyn) or byother mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of blindness related toretinal vascularization.

The compounds of this invention are also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, a component of NF-1is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certainviral infections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine,1:541-545(1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. American Journal ofPathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal,2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungalinfections.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the instant compounds may be useful in combination with knownanti-cancer and cytotoxic agents. Similarly, the instant compounds maybe useful in combination with agents that are effective in the treatmentand prevention of NF-1, restinosis, polycystic kidney disease,infections of hepatitis delta and related viruses and fungal infections.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's blood-stream by local bolus injection.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase to famesylatethe substrate, the chemical content of the assay mixtures may bedetermined by well known immunological, radiochemical or chromatographictechniques. Because the compounds of the instant invention are selectiveinhibitors of FPTase, absence or quantitative reduction of the amount ofsubstrate in the assay mixture without the compound of the instantinvention relative to the presence of the unchanged substrate in theassay containing the instant compound is indicative of the presence ofFPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

Example 1 1-(2- Pyrid-2-yl!pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole

Step A: 2-Trifluoromethanesulfonyloxy-5-pyridine carboxylic acid

To a solution of 2-hydroxy 5-pyridine carboxylic acid (185 mg, 1.33mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane(7 mL) at -78° C. is added trifluoromethanesulfonic anhydride (0.224 mL,1.33 mmol) and the mixture stirred at -78° C. for 1 hour and then atambient temperature for 1 hour. The reaction is diluted with water andextracted with CH₂ Cl₂, and the organic extract is dried, (MgSO4) andthe solvent is evaporated in vacuo. The residue is purified bychromatography to afford the title compound.

Step B: 2-(Pyrid-2-yl)-5-pyridine carboxylic acid

A mixture of 2-trifluoromethanesulfonyloxy-5-pyridine-carboxylic acid(0.442 g, 1.72 mmol), 2-pyridylboronic acid (1.57 g, 12.79 mmol), bariumhydroxide (0.813 mg, 2.58 mmol), DME (8 mL) and water (1.5 mL) is purgedwith dry argon. Tetrakis(triphenylphosphine) palladium(0) (99.0 mg,0.086 mmol) is added, and the resultant solution is stirred at 80° C.for 4 hours. The solvents are evaporated in vacuo, and the residue ispartitioned between EtOAc and water. The aqueous extract is separated,and extracted with EtOAc. The organic extracts are combined, washed withsat. aq. NaHCO₃ and 5% aq. Na₂ S₂ O₃, dried, (Na₂ SO₄) and the solventis evaporated in vacuo. The residue is purified by chromatography toafford the title compound.

Step C: 2-(Pyrid-2-yl)-5-hydroxymethyl-pyridine

To a solution of 2-(pyrid-2-yl)-5-pyridine carboxylic acid (0.320 g,1.60 mmol) in THF (5 mL) at 0° C. is added 1.0M lithium aluminum hydridein diethyl ether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction isallowed to stir at ambient temperature for 3 hours, cooled to 0° C., andwater (0.10 mL), 4N aq. NaOH (0.10 mL), and water (0.30 mL) are addedsequentially. The reaction is filtered through a pad of Celite and thefiltrate is evaporated in vacuo. The residue is purified bychromatography to afford the title compound.

Step D: 1-(2-(Pyrid-2-yl) pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole

To a solution of 2-(pyrid-2-yl)-5-hydroxymethyl-pyridine (269 mg, 1.33mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane(7 mL) at -78° C. is added trifluoromethanesulfonic anhydride (0.224 mL,1.33 mmol) and the mixture stirred at -78° C. for 1 hour. To thismixture is added a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warmto ambient temperature and stirred for 2 hours. The solvent isevaporated in vacuo. The residue is dissolved in methanol (50 mL),heated at reflux for 1 hour, and the solvent is evaporated in vacuo. Theresidue is partitioned between dichloromethane and sat. aq. NaHCO₃solution. The organic layer is dried, (Na₂ SO₄) and the solventevaporated in vacuo. The residue is chromatographed to afford the titlecompound.

Example 2N-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-5-(pyrid-2-yl)-2-amino-pyrimidine

Step A: 5-(Pyrid-2-yl)-2-aminopyrimidine

A mixture of 2-amino-5-bromopyrimidine (0.299 g, 1.72 mmol),2-pyridylboronic acid (1.57 g, 12.79 mmol), barium hydroxide (0.813 mg,2.58 mmol), DME (8 mL) and water (1.5 mL) is purged with dry argon.Tetrakis(triphenylphosphine) palladium(0) (99.0 mg, 0.086 inmol) isadded, and the resultant solution is stirred at 80° C. for 4 hours. Thesolvents are evaporated in vacuo, and the residue is partitioned betweenEtOAc and water. The aqueous extract is separated, and extracted withEtOAc. The organic extracts are combined, washed with sat. aq. NaHCO₃and 5% aq. Na₂ S₂ O₃, dried, (Na₂ SO₄) and the solvent is evaporated invacuo. The residue is purified by chromatography to afford the titlecompound.

Step B: 1-Triphenylmethyl-4-(hydroxymethyl)imidazol

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260mmol) in dry DMF (250 mL) at room temperature was added triethylamine(90.6 mL, 650 mmol). A white solid precipitated from the solution.Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL) was addeddropwise. The reaction mixture was stirred for 20 hours, poured overice, filtered, and washed with ice water. The resulting product wasslurried with cold dioxane, filtered, and dried in vacuo to provide thetitled product as a white solid which was sufficiently pure for use inthe next step.

Step C: 1-Triphenylmethyl-4-(acetoxymethyl)-imidazole

The alcohol from Step B (260 mmol, prepared above) was suspended inpyridine (500 mL). Acetic anhydride (74 mL, 780 mmol) was addeddropwise, and the reaction was stirred for 48 hours during which itbecame homogeneous. The solution was poured into EtOAc, washedsequentially with water, 5% aq. HCl solution, sat. aq. NaHCO₃, solution,and brine. The organic extracts were dried, (Na₂ SO₄), and concentratedin vacuo to provide the product as a white powder, which wassufficiently pure for use in the next reaction.

Step D: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide

A solution of the product from Step C (85.8 g, 225 mmol) and4-cyanobenzyl bromide (50.1 g, 232 mmol) in EtOAc (500 mL) was stirredat 60° C. for 20 hours, during which a pale yellow precipitate formed.The reaction was cooled to room temperature and filtered to provide thesolid imidazolium bromide salt. The filtrate was concentrated in vacuoto a volume (200 mL), heated at 60° C. for 2 hours, cooled to roomtemperature, and filtered. The filtrate was concentrated in vacuo to avolume (100 mL), heated at 60° C. for 2 hours, cooled to roomtemperature, and concentrated in vacuo to provide a pale yellow solid.All of the solid material was combined, dissolved in methanol (500 mL),and warmed to 60° C. After 2 hours, ithe solution was concentrated invacuo to provide a white solid which was triturated with hexane toremove soluble by products. Removal of residual solvents in vacuoprovided the titled product as a white solid which was used in the nextstep without further purification.

Step E: 1-(4-Cyanobenzyl)-5-(hydroxymethyl)-imidazole

To a solution of the acetate from Step D (50.4 g, 150 mmol) in 3:1THF/water (1.5 L) at 0° C. was added lithium hydroxide monohydrate (18.9g, 450 mmol). After 1 hour, the reaction was concentrated in vacuo,diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO₃ andbrine. The solution was then dried (Na₂ SO₄), filtered, and concentratedin vacuo to provide the crude product as a pale yellow fluffy solidwhich was sufficiently pure for use in the next step without furtherpurification.

Step F: 1-(4-Cyanobenzyl)-5-(chloromethyl)-imidazol

A solution of 1-(4-cyanobenzyl)-5-(hydroxymethyl)-imidazole (1.00 g,4.70 mmol), in thionyl chloride (5 mL), was stirred at 70° C. for 16hours. The solvent was evaporated in vacuo and the resulting solidsuspended in CH₂ Cl₂, collected by filtration and dried in vacuo. Thematerial was sufficiently pure for use in the next step without furtherpurification.

¹ H NMR (CD₃ OD 400 MHz) δ 9.06 (1H, s), 7.83(2H, d, J=8.0 Hz), 7.77(1H,s), 7.55(2H, d, J=8.0 Hz), 5.67(2H, s) and 4.78(2H, s) ppm.

Step G:N-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-5-(pyrid-2-yl)-2-aminopyrimidine

To a solution of the chloride from step F (500 mg, 1.65 mmol) in DMF (10mL) at 0° C. is added sequentially, the amine from step A (284 mg, 1.65mmol) and sodium hydride (145 mg, 60% dispersion in mineral oil, 3.62mmol). Stirring is continued at 0° C. for 1 hour and then at roomtemperature for 16 hours. The reaction is quenched with water (50 mL),and extracted with CH₂ Cl₂. The organic extracts are dried, (MgSO4), andthe solvent is evaporated in vacuo. The residue is purified bychromatography to afford the title compound

Example 3 In vitro inhibition of ras farnesyl transferase

Assays offarnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM ³ H!-farnesyl diphosphate ( ³ H!-FPP; 740CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at31 ° C. for 60 min. Reactions were initiated with FPTase and stoppedwith 1 ml of 1.0M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach II cell harvestor, washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the ³ H!-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention are tested for inhibitoryactivity against human FPTase by the assay described above.

Example 4 In vivo ras famesylation assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supplemeted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi ³⁵ S!methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaCl) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfamesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

Example 5 In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits farnesyl-proteintransferase of the formula A: ##STR27## wherein: one f is N or N→O, andthe remaining f's are independently CH;one g is N or N→O, and theremaining g's are independently CR⁶ ; R¹ and R² are independentlyselected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,R¹¹ C(O)O--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted or substituted C₁-C₆ alkyl wherein the substituent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, heterocyclic, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ --, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R³, R⁴ and R⁵ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;each R⁶ is independently selected from:a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; orany two of R⁶ on adjacent carbon atoms arecombined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --; provided that when R³, R⁴,R⁵ or R⁶ is unsubstituted or substituted heterocycle, attachment of R³,R⁴, R⁵, or R⁶ to the 6-membered heteroaryl ring, is through asubstitutable heterocycle ring carbon; R⁷ is selected from: H; C₁₋₄alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl,arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:a)C₁₋₄ alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ##STR28## f)--SO₂ R¹¹ g) N(R¹⁰)₂ or h) C₁₋₄ perfluoroalkyl; R⁸ is independentlyselected from:a) hydrogen, b) aryl, substituted aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a substitutable ring carbon; R⁹ is independently selectedfrom:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, Br, R¹¹ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byperfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; A¹ and A² are independentlyselected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --,--NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,providedthat V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ isa bond, n is 0 and A² is S(O)_(m) ; provided that when V is heterocycle,attachment of V to R⁸ and to A¹ is through a substitutable ring carbon;W is a heterocycle; X is a bond, --CH═CH--, O, --C(═O)--, --C(O)NR⁷ --,--NR⁷ C(O)--, --C(O))--, --OC(O)--, --C(O)NR⁷ C(O)--, --NR⁷ --, --S(O)₂N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --; m is 0, 1 or 2; n isindependently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is0, 1, 2or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and tis 1,or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1 of the formula A: ##STR29## wherein: one f is N orN→O, and the remaining f's are independently CH;one g is N or N→O, andthe remaining g's are independently CR⁶ ; R¹ is independently selectedfrom: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) unsubstituted or substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³, R⁴ and R⁵ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl; d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; each R⁶ is independently selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl; d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R⁶ on adjacent carbon atoms arecombined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;provided that when R³, R⁴,R⁵ or R⁶ is unsubstituted or substituted heterocycle, attachment of R³,R⁴, R⁵, or R⁶ to the 6-membered heteroaryl ring, is through asubstitutable heterocycle ring carbon; R⁷ is selected from: H; C₁₋₄alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl,arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:a)C₁₋₄ alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ##STR30## f)--SO₂ R¹¹ g) N(R¹⁰)₂ or h) C₁₋₄ perfluoroalkyl; R⁸ is independentlyselected from:a) hydrogen, b) aryl, substituted aryl, heterocycle, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl,R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁-C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;provided that when R⁸ isheterocycle, attachment of R⁸ to V is through a substitutable ringcarbon; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹¹ 10--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; R¹² is independentlyselected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substitutedaralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl,substituted aryl, heteroaryl, substituted heteraryl, C₁ -C₆perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; V is selected from:a)hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl,imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl,isoquinolinyl, triazolyl and thienyl, c) aryl, d) C₁ -C₂₀ alkyl whereinfrom 0 to 4 carbon atoms are replaced with a heteroatom selected from O,S, and N, and e) C₂ -C₂₀ alkenyl, and provided that V is not hydrogen ifA¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; provided that when V is heterocycle, attachment of V to R⁸and to A¹ is through a substitutable ring carbon; W is a heterocycleselected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl,thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl; Xis a bond, O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷ C(O)--, --NR⁷--, --S(O)₂ N(R¹⁰)--, --N(R¹ l)S(O)₂ -- or --S(═O)_(m) --; m is 0, 1 or2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or4; q is 0, 1, 2 or 3; r is 0 to 5, provided that r is 0 when V ishydrogen; and t is 1;or a pharmaceutically acceptable salt thereof. 3.The compound according to claim 1 of the formula B: ##STR31## wherein:one f is N or N-→O, and the remaining f's are independently CH;one g isN or N-→O, and the remaining g's are independently CR⁶ ; R¹ isindependently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--,--N(R¹⁰)₂, F or C₁ -C₆ alkyl; R² is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂,F or C₂ -C₆ alkenyl, c) unsubstituted or substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³ and R⁴ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; each R⁶ is independently selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; orany two of R⁶ on adjacent carbon atoms arecombined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --; provided that when R³, R⁴or R⁶ is unsubstituted or substituted heterocycle, attachment of R³, R⁴or R⁶ to the 6-membered heteroaryl ring, is through a substitutableheterocycle ring carbon; R⁸ is independently selected from:a) hydrogen,b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰, andc) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰, (R¹⁰)₂ N--C(NR¹⁰), R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--;provided that when R⁸ is heterocycle, attachment of R⁸ to V isthrough a substitutable ring carbon; R^(9a) and R^(9b) are independentlyhydrogen, C₁ -C₆ alkyl, trifluoromethyl and halogen; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl; R¹¹ is independently selected from C₁ -C₆alkyl and aryl; R¹² is independently selected from hydrogen, C₁ -C₆alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl,C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl; A¹ and A² are independently selected from: a bond,--CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a substitutablering carbon;X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰--, O or --C(═O)--; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4;p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V ishydrogen;or a pharmaceutically acceptable salt thereof.
 4. The compoundaccording to claim 1 of the formula C: ##STR32## wherein: one f is N orN→O, and the remaining f's are independently CH;one g is N or N→O, andthe remaining g's are independently CR⁶ ; R¹ is independently selectedfrom: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) unsubstituted or substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³ and R⁴ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ C(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; each R⁶ is independently selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; orany two of R⁶ on adjacent carbon atoms arecombined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --; provided that when R³, R⁴or R⁶ is unsubstituted or substituted heterocycle, attachment of R³, R⁴or R⁶ to the 6-membered heteroaryl ring, is through a substitutableheterocycle ring carbon; R⁸ is independently selected from:a) hydrogen,b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;provided that when R⁸ is heterocycle, attachment of R⁸ to Vis through a substitutable ring carbon; R^(9a) and R^(9b) areindependently hydrogen, C₁ -C₆ alkyl, trifluoromethyl and halogen; R¹⁰is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl; R¹¹ is independently selected from C₁ -C₆alkyl and aryl; R¹² is independently selected from hydrogen, C₁ -C₆alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl,C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl; A¹ and A² are independently selected from: a bond,--CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a substitutablering carbon;X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰--, O or --C(═O)--; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4;p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O; andr is 0 to 5, provided that r is 0 when V is hydrogen;or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 3 of the formula D: ##STR33## wherein: one f is N or N→O, and theremaining f's are independently CH;one g is N or N→O, and the remainingg's are independently CR⁶ ; R¹ is independently selected from: hydrogen,C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl; R² is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂,F or C₂ -C₆ alkenyl, c) C₁ -C₆ alkyl unsubstituted or substituted byaryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or--N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹¹ C(O)--, N₃, --N(R¹⁰)₂, and R¹⁰ C(O)--NR¹⁰ --; R⁴is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ; each R⁶ isindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;orany two of R⁶ on adjacent carbon atoms are combined to form adiradical selected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ --and --(CH₂)₃ --; provided that when R³ or R⁶ is unsubstituted orsubstituted heterocycle, attachment of R³ or R⁶ to the 6-memberedheteroaryl ring, is through a substitutable heterocycle ring carbon; R⁸is independently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroaLkyl, R¹⁰ --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;providedthat when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon; R^(9a) and R^(9b) are independently hydrogen,halogen, CF₃ or methyl; R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; A¹ is selected from: a bond,--C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ; X is a bond, --CH═CH--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or --C(═O)--; n is 0 or 1;provided that n is not 0 if A¹ is a bond, O, --N(R¹⁰)-- or S(O)_(m) ;mis 0, 1 or 2; and p is 0, 1, 2, 3 or 4;or a pharmaceutically acceptablesalt thereof.
 6. The compound according to claim 4 of the formula E:##STR34## wherein: one f is N or N→O, and the remaining f's areindependently CH;one g is N or N→O, and the remaining g's areindependently CR⁶ ; R¹ is independently selected from: hydrogen, C₃ -C₁₀cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl; R² is independentlyselected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₂ -C₆ alkenyl, c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,R¹⁰ O--, or --N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ I OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃; each R⁶ is independently selected from:a) hydrogen, b) unsubstitutedor substituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹⁰ C(O)--NR¹⁰ --;orany two of R⁶ on adjacent carbon atoms are combined to form adiradical selected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ --and --(CH₂)₃ --; provided that when R³ or R⁶ is unsubstituted orsubstituted heterocycle, attachment of R³ or R⁶ to the 6-memberedheteroaryl ring, is through a substitutable heterocycle ring carbon; R⁸is independently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;providedthat when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon; R^(9a) and R^(9b) are independently hydrogen,halogen, CF₃ or methyl; R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, --CH═CH--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or --C(═O)--; n is 0 or 1;mis 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X isa bond or O;or a pharmaceutically acceptable salt thereof.
 7. Thecompound according to claim 5 of the formula F: ##STR35## wherein: one fis N or N→O, and the remaining f's are independently CH;one g is N orN→O , and the remaining g's are independently CR⁶ ; R¹ is independentlyselected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl; R² isindependently selected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F, c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, or--N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R⁴is selected from H, halogen, CH₃ and CF₃ ; each R⁶ is independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹⁰ C(O)--NR¹⁰ --; orany two of R⁶ on adjacent carbon atoms are combinedto form a diradical selected from --CH═CH--CH═CH--, --CH═CH--CH₂ --,--(CH₂)₄ -- and --(CH₂)₃ --; provided that when R³ or R⁶ isunsubstituted or substituted heterocycle, attachment of R³ or R⁶ to the6-membered heteroaryl ring, is through a substitutable heterocycle ringcarbon; R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ ormethyl; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; R¹² is independently selected from hydrogen,C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl,heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyland 2,2,2-trifluoroethyl; X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰C(O)--, --NR¹⁰ --, O or --C(═O)--;m is 0, 1 or 2; and p is 0, 1, 2, 3 or4;or a pharmaceutically acceptable salt thereof.
 8. The compoundaccording to claim 6 of the formula G: ##STR36## wherein: one f is N orN→O, and the remaining f's are independently CH;one g is N or N→O, andthe remaining g's are independently CR⁶ ; R¹ is independently selectedfrom: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle or C₃ -C₁₀ cycloalkyl c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,R¹⁰ O--, or --N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, CH₃ and CF₃ ; eachR⁶ is independently selected from:a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;orany two of R⁶ on adjacent carbon atoms are combined to form adiradical selected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ --and --(CH₂)₃ --; provided that when R³ or R⁶ is unsubstituted orsubstituted heterocycle, attachment of R³ or R⁶ to the 6-memberedheteroaryl ring, is through a substitutable heterocycle ring carbon;R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl; R¹¹ is independently selected from C₁ -C₆alkyl and aryl; R¹² is independently selected from hydrogen, C₁ -C₆alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl,C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl; A¹ is selected from: a bond, --C(O)--, O,--N(R¹⁰)--, or S(O)_(m) ;m is 0, 1 or 2; and n is 0 or 1;or thepharmaceutically acceptable salts thereof.
 9. A compound which inhibitsfarmesyl-protein transferase which is:1-(2-Pyrid-2-yl!pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole ##STR37## or apharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a pharmaceutical carrier, and dispersed therein,a therapeutically effective amount of a compound of claim
 1. 11. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 3. 12. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 4. 13. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 9. 14. A method for inhibitingfarnesyl-protein transferase which comprises administering to a mammalin need thereof a therapeutically effective amount of a composition ofclaim
 10. 15. A method for inhibiting farmesyl -protein transferasewhich comprises administering to a mammal in need thiereof atherapeutically effective amount of a composition of claim
 11. 16. Amethod for inhibiting farnesyl-protein transferase which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 12. 17. A method for inhibitingfarnesyl-protein transferase which comprises administering to a mammalin need thereof a therapeutically effective amount of a composition ofclaim
 13. 18. A pharmaceutical composition made by combining thecompound of claim 1 and a pharmaceutically acceptable carrier.
 19. Aprocess for making a pharmaceutical composition comprising combining acompound of claim 1 and a pharnaceutically acceptable carrier.